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Decrease in total protein level of Bruton’s tyrosine kinase during ibrutinib therapy in chronic lymphocytic leukemia lymphocytes

Leukemia volume 30, pages 1803–1804 (2016)Cite this article

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Bruton’s tyrosine kinase (BTK) is a pivotal protein in the B-cell antigen receptor pathway.1 Investigations in murine hematopoietic cells demonstrated that BTK is expressed in B lymphocytes but not in T cells. This signal transducing protein is present in hematopoietic stem cells and expressed throughout the development of B cells, including in mature B-cells. However, compared with B cells in the bone marrow, peripheral blood B-lymphocytes express lower total amount of BTK protein. These observations suggest that expression of BTK protein is context dependent.2 Furthermore, activation of the B-cell antigen receptor pathway resulted in a dramatic increase in the expression of BTK in murine B cells in vitro and in intact animal model systems.3 Mechanistically, this upregulation was at the protein, not mRNA level, and was mediated through the PI3Kdelta axis. Consequently, a pan-PI3K inhibitor decreased B-cell antigen receptor-mediated increase in BTK protein level.

Recently, there has been a renewed interest in BTK because of the emergence of a small molecule inhibitor (ibrutinib) that irreversibly binds to cysteine-481 residue of the protein. Importantly, the drug showed remarkable overall response rates and improved survival in previously treated4 and untreated5 patients with chronic lymphocytic leukemia (CLL), a mature B-cell neoplasm. In fact, because of the high response rates and prolongation of survival observed without much toxicity, the drug is now FDA-approved for patients with CLL. Pharmacodynamic correlative studies, conducted in the context of a phase I trial of this oral drug, demonstrated almost complete (>95%) occupancy of cellular BTK protein at doses of ⩾2.5 mg/kg/day.6 This high occupancy of BTK by irreversible binding of the drug was a requirement for clinical response. This underscores the importance of BTK in B-cell CLL in general and levels of total protein for pharmacodynamic inhibition in particular. A unique and key feature observed in clinical trials is an egress of leukemia cells from lymph nodes to the peripheral blood resulting in a dramatic increase in the circulating lymphocyte count paralleled by a decrease in lymphadenopathy.

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Acknowledgements

We thank Benjamin Hayes and Mark Nelson for coordinating sample distribution during therapy. This work was supported in part by MD Anderson CLL Moon Shot Program and Sponsored Research Agreement form Pharmacyclics, Inc.

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  1. Department of Experimental Therapeutics, Houston, TX, USA

    F Cervantes-Gomez, V Kumar Patel & V Gandhi

  2. Department of Leukemia, The University of Texas M D Anderson Cancer Center, Houston, TX, USA

    P Bose, M J Keating & V Gandhi

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  1. F Cervantes-Gomez
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Correspondence to V Gandhi.

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VG has a sponsored research agreement with Pharmacyclics, Inc. Other authors do not have any conflict of interest.

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Cervantes-Gomez, F., Kumar Patel, V., Bose, P. et al. Decrease in total protein level of Bruton’s tyrosine kinase during ibrutinib therapy in chronic lymphocytic leukemia lymphocytes. Leukemia 30, 1803–1804 (2016). https://doi.org/10.1038/leu.2016.129

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